tbuckley/cabot-search huggingface dataset:
P364: DONOR-DERIVED CD19 CAR-T CELLS AND CHEMOTHERAPY PLUS DONOR LYMPHOCYTE INFUSION IN THE TREATMENT OF RECURRENT CD19+ B-ALL AFTER ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION
Authors: X. Tan, C. Zhang, L. Gao, L. Gao, P. Kong, Q. Wen, S. Lou, X. Zhang
Journal: HemaSphere (2022)

Background: Donor derived CD19 car T cells plus donor lymphocyte infusion is rarely used in the treatment of recurrent CD19 positive B-ALL after allogeneic hematopoietic stem cell transplantation (allo-HSCT) Aims: To compare the efficacy of donor derived CD19 car T cells and chemotherapy plus donor lymphocyte infusion in the treatment of recurrent CD19 positive B-ALL after allogeneic hematopoietic stem cell transplantation (allo-HSCT) Methods: We retrospectively analyzed 43 patients with B-ALL who relapsed after allo-HSCT from March 2016 to November 2019，including 22 patients treated with donor derived CD19-CAR-T cells (CAR-T group) and 21 patients treated with chemotherapy plus donor lymphocyte infusion (Chemo-DLI group). Results: The rates of complete remission (77.3%) in the CAR-T group were significantly higher than those in the Chemo- DLI group (38.1%); The 1- and 2-year leukemia-free survival(LFS) in the CAR-T group and Chemo-DLI group were 54.5% vs 9.5%, 45.5% vs 4.8%, respectively. The 1- and 2-year overall survival(OS) in the CAR-T group and Chemo-DLI group were 68.2% vs 19%, 63.6%vs 9.5%, respectively. Six patients (28.6%) in the Chemo-DLI group developed grade II-IV acute graft-versus-host disease (aGVHD). Two patients (9.1%) with grade I-II aGVHD were found in the CAR-T group. The incidence of CRS in the CAR-T group was 86.4%, the grade I-II CRS was59.1%, the grade III CRS was 27.3%. There was no grade 4 CRS. Two subjects developed ≤grade-2 immune effector cell-associated neurotoxicity syndrome (ICANS). Summary/Conclusion: Compared with chemotherapy plus DLI, donor-derived CD19 CAR-T is more effective and safe in the treatment of recurrent B-ALL after allogeneic HSCT.
Durvalumab Plus Olaparib in Previously Untreated, Platinum-Ineligible Patients With Metastatic Urothelial Carcinoma: A Multicenter, Randomized, Phase II Trial (BAYOU)
Authors: Jonathan E. Rosenberg, Se Hoon Park, Vadim Kozlov, Tu V. Dao, Daniel Castellano, Jian-Ri Li, Som D. Mukherjee, Kathryn Howells, Hannah Dry, Mark C. Lanasa, Ross Stewart, Dean F. Bajorin
Journal: Journal of Clinical Oncology (2022)

Homologous recombination repair gene mutations (HRRm) are common in urothelial carcinoma (UC), rendering tumor cells sensitive to poly (ADP-ribose) polymerase (PARP) inhibition. We assessed efficacy and safety of durvalumab (anti-programmed cell death ligand-1) plus olaparib (PARP inhibitor) in patients with metastatic UC (mUC).This randomized, multicenter, double-blind, phase II trial enrolled untreated, platinum-ineligible patients with mUC. Patients (N = 154) were randomly assigned 1:1 to receive durvalumab (1,500 mg intravenously once every 4 weeks) plus olaparib (300 mg orally, twice daily) or durvalumab plus placebo. The primary end point was progression-free survival (PFS) assessed by investigators per RECIST version 1.1. Secondary end points included overall survival in all patients and PFS in patients with HRRm.Overall, median PFS was 4.2 months (95% CI, 3.6 to 5.6) for durvalumab plus olaparib and 3.5 months (95% CI, 1.9 to 5.1) for durvalumab plus placebo (hazard ratio [HR], 0.94; 95% CI, 0.64 to 1.39; log-rank P value, .789). Median overall survival was 10.2 months (95% CI, 7.0 to 13.9) and 10.7 months (95% CI, 7.2 to 17.3), respectively (HR, 1.07; 95% CI, 0.72 to 1.61). In the 20% of patients with HRRm, median PFS was 5.6 months (95% CI, 1.9 to 8.1) and 1.8 months (95% CI, 1.7 to 2.2), respectively (HR, 0.18; 95% CI, 0.06 to 0.47). Treatment-related grade 3 or 4 adverse events occurred in 18% and 9% of patients, respectively.Adding olaparib to durvalumab did not improve survival outcomes in an unselected mUC population. Efficacy outcomes with durvalumab were similar to those reported for other anti-programmed cell death-1/programmed cell death ligand-1 agents. However, the results of secondary analyses suggest a potential role for PARP inhibition in patients with UC harboring HRRm.
P1181: REAL-WORLD CHARACTERISTICS AND CLINICAL OUTCOMES IN RELAPSE/REFRACTORY DIFFUSE LARGE B-CELL LYMPHOMA POST CAR-T FAILURE
Authors: C. Flores Avile, L. Liao, L. Wilson, A. Lau, L. Chen
Journal: HemaSphere (2022)

Background: Progressive disease following chimeric antigen receptor T-cell (CAR-T) therapy for diffuse large B-cell lymphomas (DLBCL) is a common scenario. There are limited treatment options after CAR-T failure with a poor prognosis for patients at this stage in their disease. The effectiveness of existing treatment options following CAR-T failure is still being investigated in the real-world setting. Aims: To further understand the clinical outcomes of CAR-T failure in relapse/refractory (RR) DLBCL patients in the real-world setting. Methods: This retrospective analysis identified adult patients diagnosed with RR-DLBCL [01/01/2014 – 03/31/2021] who received CAR-T therapy and experienced a subsequent disease progression or death. COTA's Real World Evidence (RWE) database is comprised of longitudinal, HIPAA-compliant data abstracted from electronic health records (EHR) from over 200 sites of care in US (60% academic, 40% community). The first post CAR-T therapy was categorized as checkpoint inhibitor +/- other therapies (CPI), investigational therapies, tafasitamab +/- lenalidomide, polatuzumab-containing regimen (pola-containing), lenalidomide +/- anti-CD20, BTK inhibitors (BTKi), chemotherapy/chemoimmunotherapy (CT/CIT), allogenic stem-cell transplant (allo-SCT), or anti-CD20 monoclonal antibody. Overall response rate (ORR), complete response (CR), and overall survival (OS) were reported for treatment groups with at least 5 patients. Results: Of the 97 CAR-T patients identified, 57 (59%) patients failed CAR-T therapy due to receiving subsequent line of therapy, having documented progression event, or death. Patients who failed CAR-T were 67% male and on average 59 years old. Within a median follow-up of 12.4mo, 44 (77%) initiated further therapy whereby 7 (16%) initiated investigational therapies, 9 (20%) CPI, 7 (16%) tafasitamab +/- lenalidomide, 6 (14%) pola-containing, 5 (11%) lenalidomide +/- anti-CD20, 3 (7%) CT/CIT, 3 (7%) anti-CD20 monoclonal antibody, 2 (5%) BTKi, and 2 (5%) allo-SCT as their first post CAR-T therapy. Of these patients, 48% received more than two lines of therapies after CAR-T. Response rates of select first therapies received after CAR-T are detailed in Table 1. Outside clinical trials, ORR and CRs were highest for lenalidomide +/- anti CD20 (60% & 20%), followed by CPI (33% & 0%), pola-containing (33% & 0%) and tafasitamab +/- lenalidomide (14% & 0%). OS of first post CAR-T therapy was highest for lenalidomide+/- anti CD20 (12.5 mo), then CPI (11 mo), pola-containing therapy (6.37 mo), and tafasitamab +/- lenalidomide (2.7 mo). Image:Summary/Conclusion: There is no existing standard of care after patients fail CAR-T therapy. Although further research is warranted in a larger sample population, poor clinical outcomes in treatment response and longevity were observed with existing treatment options. There is still a high unmet need for more effective therapies after CAR T-cell therapy has failed.
P459: NUC-7738 REGULATES BETA-CATENIN SIGNALLING RESULTING IN REDUCED PROLIFERATION AND SELF-RENEWAL OF AML CELLS
Authors: A. M. Shahid, M. Elshani, D. J. Harrison
Journal: HemaSphere (2022)

Background: NUC-7738, a phosphoramidate transformation of 3’deoxyadenosine (3’dA), is specifically designed to generate the active anti-cancer metabolite 3’-deoxyadenosine triphosphate (3’-dATP) directly in cells, bypassing key cancer resistance mechanisms of transport, activation and breakdown. NUC-7738 is currently in a Phase I/II clinical study to assess safety and determine the recommended dose in patients with advanced solid tumors and lymphoma. We have recently shown in cell lines a potential therapeutic role for NUC-7738 in patients with acute myeloid leukemia (AML), whereby NUC-7738 induced myeloid cell differentiation and mitochondrial-mediated apoptosis. AML leukemia stem cells (LSCs) are required for the initiation and maintenance of the disease. Activation of the Wnt/β-catenin pathway is required for the survival and development of LSCs and therefore, targeting β-catenin is a potential therapeutic strategy. Aims: The aim of this study was to determine whether NUC-7738 regulates β-catenin and the expression of its target genes in AML cells Methods: AML cell lines KG1a, OCI-AML3, HL-60 and U937 were treated with NUC-7738 for 48 or 72 hours. LSCs were determined by the expression of surface markers CD34, CD38 and CD123 via flow cytometry. Self-renewal was assessed by performing the colony forming assay using MethoCult Enriched media. Cell proliferation was determined by the Alamar Blue assay. Immunoblotting was performed for β-catenin, PI3K-p110, phosphorylated AktSer473 and phosphorylated GSK3βSer9 Results: NUC-7738 reduced PI3K-p110, phosphorylated AktSer473 and phosphorylated GSK3βSer9 resulting in reduced β-catenin expression. NUC-7738 decreased the percentage of CD34+ CD38- CD123+ (LSCs) from 15% to 7% and significantly reduced the total number and size of leukemic colonies. NUC-7738 inhibited cell proliferation in U937, OCI-AML3 and HL-60 cells, with IC50’s of 1.55 µM, 7 µM and 16 µM, respectively. Summary/Conclusion: Self-renewal pathways, including Wnt/β-catenin, are key for the initiation and long-term maintenance of LSCs. Through the ability to reduce PI3K-p110, phosphorylated AktSer473, and phosphorylated GSK3βSer9 and suppress β-catenin signalling, NUC-7738 exploits a key developmental process of AML, supressing the expansion and survival of LSCs. These results indicate that targeting LSCs with NUC-7738 may offer a successful therapeutic strategy for treating patients with leukemia.
P1391: COMPARISON OF AUTOLOGOUS AND ALLOGENEIC STEM CELL TRANSPLANTATION FOR ADULT PATIENTS WITH PHILADELPHIA CHROMOSOME-NEGATIVE ACUTE LYMPHOBLASTIC LEUKEMIA IN FIRST COMPLETE REMISSION
Authors: R. Zhang, M. Lv, D. Yang, A. Pang, W. Zhai, X. Chen, Q. Ma, Y. He, J. Wei, E. Jiang
Journal: HemaSphere (2022)

Background: Adult Philadelphia chromosome-negative acute lymphoblastic leukemia (Ph- ALL) is a high-risk subtype of acute leukemia and allogeneic hematopoietic stem cell transplantation (Allo-HSCT) is still the standard consolidation therapy for patients with available donors. With the intensive consolidation chemotherapy and the accuracy of minimal residual disease (MRD)，auto-SCT also can be used for eligible patients. Aims: To analyze the outcomes of patients who received autologous stem cell transplantation (auto-SCT) or Allo-HSCT and provide the basis for the choice of transplantation method in Ph- ALL in first complete remission. Methods: We retrospectively investigated the outcomes of 139 adult patients PH - ALL who received stem cell transplantation with myeloablative condition regimen from January 2014 to September 2021 in our center. The overall survival (OS) rate, leukemia-free survival (LFS) rate, cumulative incidence of relapse (CIR) rate and non-relapse mortality (NRM) rate were explored. Results: The median follow-up time was 23 (2-96.5) months with a total of 33 patients dead and 34 patients relapsed among the 139 patients and the 3 years OS, LFS, CIR and NRM rates after transplantation were 71.7 ± 4.6%, 61.3 ± 4.5%, 27.2 ± 4.1%,11.2 ± 2.9%, respectively. Both positive MRD after 3 courses of chemotherapy and MRD-positive before transplantation were poor prognostic factors for LFS and RR. For the 98 patients who achieved MRD negative after 3 courses of chemotherapy, there was no significant difference in OS(82.8% vs 72.3%，P=0.119)，LFS(66.4% vs 64.3%，P=0.690), CIR(27.1% vs 17.1%，P=0.237）between auto-SCT group and allo-HSCT group, while auto-SCT group showed lower NRM (2.5% vs. 18.6 %, P= 0.028) than the allo-HSCT group. However, for the 41 patients who remained MRD positive after 3 courses of chemotherapy, the auto-SCT group had higher CIR (66.7% vs 36.8%, P= 0.021) than the allo-HSCT group. Image:Summary/Conclusion: For Ph-negative ALL patients who obtain MRD-negative after 3 courses of chemotherapy, autologous hematopoietic stem cell transplantation is an effective consolidation therapy option and maintenance chemotherapy after transplantation is important toreduce recurrence, and for patients with MRD-positive after 3 courses of chemotherapy, allogeneic hematopoietic stem cell transplantation is an effective means to reduce relapse and improve survival.
Results from a nationwide retrospective cohort measure the impact of C3 and soluble C5b-9 levels on kidney outcomes in C3 glomerulopathy
Authors: Sophie Chauvet, Jill J. Hauer, Florent Petitprez, Marion Rabant, Paula Vieira Martins, Véronique Baudouin, Yahsou Delmas, Noémie Jourde-Chiche, Alexandre Cez, David Ribes, Sylvie Cloarec, Aude Servais, Mohamad Zaidan, Eric Daugas, Michel Delahousse, Alain Wynckel, Amélie Ryckewaert, Anne Laure Sellier-Leclerc, Olivia Boyer, Eric Thervet, Alexandre Karras, Richard J.H. Smith, Véronique Frémeaux-Bacchi
Journal: Kidney International (2022)
Auranofin attenuates hepatic steatosis and fibrosis in nonalcoholic fatty liver disease via NRF2 and NF- κB signaling pathways
Authors: Seung Min Lee, Dong Hee Koh, Dae Won Jun, Yoon Jin Roh, Hyeon Tae Kang, Ju Hee Oh, Hyun Sung Kim
Journal: Clinical and Molecular Hepatology (2022)

Background/Aims: We aim to evaluate the effects of auranofin, a known antioxidant, on hepatic steatosis, inflammation, and fibrosis, contributing to non-alcoholic steatohepatitis (NASH) development in vivo and in vitro.Methods: Transcriptome analysis of LX-2 cells was that expression patterns of genes changed by auranofin, and their related pathways were estimated. We used the gene set enrichment analysis (GSEA) program to determine the pathway involved in overall genetic change. &lt;i&gt;In vitro&lt;/i&gt;, LX-2 and HepG2 cells were treated with transforming growth factor (TGF)-β1 and palmitic acid (PA), respectively, and the antifibrotic and antiadipogenic effect function of auranofin was evaluated.Results: Transcriptome analysis revealed that auranofin decreased the expression of 15 genes, including thrombospondin 1, endothelin 1 (ET-1), fibronectin 1, and LOX. The molecular functions of these genes are involved in collagen binding. GSEA of the overall gene expression pattern revealed that many genes increased in the reactive oxygen species pathway and decreased in the inflammatory response. Auranofin decreased nuclear factor kappa B (NF-κB) and IκBα in TGF-β1-induced LX-2 cells, thereby reducing ET-1 and fibrosis. Furthermore, increased pNRF2 in PA-induced HepG2 cells led to increased antioxidant marker expression and decreased lipid accumulation. In the bile duct ligation model mice, auranofin reduced the fibrosis area and increased the survival rate. Auranofin reduced liver fibrosis and lipid accumulation in NASH model mice fed on a Western diet.Conclusions: Auranofin inhibits lipogenesis and fibrosis formation and is a proposed candidate for NASH treatment.
Stem cell membrane, stem cell-derived exosomes and hybrid stem cell camouflaged nanoparticles: A promising biomimetic nanoplatforms for cancer theranostics
Authors: Neda Khosravi, Elham Pishavar, Behzad Baradaran, Fatemeh Oroojalian, Ahad Mokhtarzadeh
Journal: Journal of Controlled Release (2022)
Impact of Smoking on Visual Field Progression in a Long-term Clinical Follow-up
Authors: Golnoush Mahmoudinezhad, Takashi Nishida, Robert N. Weinreb, Sally L. Baxter, Medi Eslani, Eleonora Micheletti, Jeffrey M. Liebmann, Massimo A. Fazio, Christopher A. Girkin, Linda M. Zangwill, Sasan Moghimi
Journal: Ophthalmology (2022)
P742: TRANSCRIPTOMIC ANALYSIS OF ISOLATED CD4+ AND CD8+ T CELLS REVEALS DIFFERENCES IN TCR REPERTOIRE IN PATIENTS WITH HIGH RISK MDS COMPARED TO AML.
Authors: K. Katsiki, A. Tasis, A. Filia, E. Lamprianidou, K. Liapis, I. Kotsianidis, I. Mitroulis
Journal: HemaSphere (2022)

Background: Myelodysplastic syndrome (MDS) is a group of clonal disorders of hematopoietic progenitor cells, which often progresses towards acute myeloid leukemia (AML). Even though MDS is a clonal hematopoietic disease, bone marrow microenvironment and more specifically inflammation has been linked to its progression. Among other cell types, CD4+ and CD8+ T cells are major players in the regulation of the microenvironment in malignancies. Aims: In this study, we aimed to investigate the molecular signature of bone marrow CD4+ and CD8+ T cells from patients with high-risk MDS, AML and chronic myelomonocytic leukemia (CMML). Methods: RNA sequencing was performed on isolated CD4+ and CD8+ T cells from the bone marrow of six patients with high risk MDS (RAEB-II), six patients with CMML and four patients with AML, using cell sorting. Except from the analysis of gene expression, we performed TCR repertoire analysis using VDJtools, an open-source Java/Groovy-based framework that can analyze immune repertoire sequencing (RepSeq) data and allows applying a diverse set of post-analysis strategies. To do so, RNA sequencing data were used as input for the V-(D)-J junction mapping software and analysis was performed on the MiXCR platform. The output of MiXCR wereused as input for the VDJtools after running a convert routine with -S mixcr argument to prepare datasets in a format for VDJtools analysis. Results: Analysis of CD8+ T cells from patients with high risk MDS and AML identified 38 differentially expressed genes. We observed that the expression of the TCR variants TRAV20 and TRAV13-1 was increased in patients with AML compared to high risk MDS (Figure 1A). Further analysis of the TCR repertoire revealed that the diversity of TCR was higher in CD8+ T cells from patients with AML (Figure 1B), whereas multidimentional scaling analysis revealed a clear separation of the two groups (Figure 1C). To the same direction, clustering of the usage of TRAV-TRAJ further confirmed this finding (Figure 1D). On the other hand, we did not observe any difference in the TCR diversity of the variant usage when we compared CD8+ T cells from patients with CMML and AML (Figure 1E-F), or in the comparison between CD4+ T cells from patients with high risk MDS and AML (Figure 1G-I). Image:Summary/Conclusion: CD8+ T cells are a major cell population that exerts anti-tumour properties in cancer. Herein, we compared the TCR repertoire of CD8+ and CD4+ T cells in the bone marrow of patients with high risk MDS and AML and observed that despite the common features of these two disorders, there are significant differences in the TCR repertoire specifically in CD8+ T cells, especially concerning TCR diversity. These findings imply that there is more active T cell response in the bone marrow in AML compared to MDS. However, it is not clear to what degree this T cell response targets AML neo-antigens.
P1346: EVALUATION OF CURRENT NATIONAL PRACTICE IN THE PREVENTION OF PTLD POST PAEDIATRIC HSCT
Authors: E. Kissane, I. Sulevani, D. B. James
Journal: HemaSphere (2022)

Background: Post-transplant lymphoproliferative disorder (PTLD) is a rare but significant cause of mortality in paediatric patients undergoing haematopoietic stem cell transplantation (HSCT). It is typically caused by reactivation of the Epstein-Barr virus (EBV), a virus present in 95% of the adult population. Immunocompromise post-transplant enables EBV, typically passively acquired from the donor, to proliferate, with the potential for malignant transformation. HSCT recipients are at greatest risk of PTLD in the first year after transplant. Pre-emptive Rituximab, given to those with EBV reactivation, reduces the risk of PTLD. However, the level of EBV viraemia at which Rituximab should be initiated is not defined in any national or international guidelines. Aims: This prospective project aimed to understand current national practice in all twelve centres within the UK and Ireland which carry out paediatric allogenic HSCTs. These centres are: Birmingham, Bristol, Dublin, Glasgow, Great Ormond Street, Leeds, Manchester, Newcastle, Sheffield, The Royal Marsden, St.Mary’s and University College Hospital. Methods: An online survey was sent to each centre which included six questions focusing on: patient monitoring, frequency of testing, pre-emptive Rituximab thresholds and general threshold rules. Results: The survey had a 92% response rate. Regarding monitoring, nine centres monitored EBV PCR levels once weekly and two centres monitored twice weekly. Seven centres reduced the frequency of monitoring when patients reached a degree of immune reconstitution, two centres reduced monitoring when patients were discharged, and one centre had no fixed rules. Nationally there is no agreed threshold for starting pre-emptive Rituximab but 46% of centres initiated Rituximab when EBV PCR reached 40,000 copies/ml, with the second most common threshold being 20,000 copies/ml used by 18%. In patients that were symptomatic ten out of eleven centres used a lower threshold to initiate Rituximab, with nine of the ten centres beginning Rituximab on clinical symptoms alone and the remaining one centre having a threshold of 10,000 copies/ml alongside clinical symptoms. Summary/Conclusion: National practice varies, including when to initiate pre-emptive Rituximab, with the most common threshold being 40,000 copies/ml. Notably, there is no nationally agreed guideline defining EBV viraemia. Future research is needed comparing PTLD incidence between centres who use a higher threshold and those who use a lower one.